Populations with Amerindian origins such as Mexicans are highly predisposed to dyslipidemias but so far most genomic studies have mainly focused on Europeans, leaving a large biomedical knowledge gap in the most susceptible group. Abnormal serum lipid levels are key risk factors for one of the worldwide leading causes of death, cardiovascular disease (CVD). Therefore, advancement in the prevention and treatment of lipid disorders are of high medical significance, especially to the most vulnerable but underrepresented Hispanic groups. The Aim 1 of the project is to identify Hispanic-specific lipid risk variants in the known key lipid genes, LPL and its pathway, as well as in the novel lipi genes with Amerindian-specific signals such as SIK3 and RORA that we recently discovered (Ko et al. 2014 Nature Communications). To cost-effectively capture rare and structural variants in these genes in a cohort of 9,000 Mexicans ascertained for hypertriglyceridemia, we will perform targeted sequencing utilizing molecular inversion probes (MIPs). We will perform association test at the single variant level or in aggregation for common and rare variants, respectively, to increase statistical power. Risk variants that are both Mexican-specific based on the cross-population comparison with ~19,000 Europeans and display the highest cross-species conservation and functional evidence, will be carried forward for replication in a separate cohort of 12,000 Mexicans using MIPs or whole exome sequencing. Common and rare risk variants will be functionally validated via refined phenotyping of lipid metabolism in human, including oral fat tolerant (OFT) test, LPL enzymatic activity, and APOCIII protein levels. The OFT test measures the postprandial lipid clearance rate that when delayed becomes highly atherogenic, leading to CVD. The proposed refined phenotyping will help facilitate the much needed translation from genomic findings to biological insight and clinical relevance. In Aim 2, we will utilize our previos experience with RNA-sequencing (RNA-seq) and expression quantitative trait locus (eQTL) mapping (Ko et al. submitted) to profile 450 Mexican adipose tissue transcriptomes and identify population-specific transcriptional regulation, mediated by dyslipidemias. We will map eQTLs in the dyslipidemic and normolipidemic Mexicans, separately, using only the variants that display allele frequency difference between Mexicans and Europeans. These regulatory, Mexican- specific variants are functional candidates that might influence lipid metabolism via transcriptional regulation. Due to the recently demonstrated direct association between hypertriglyceridemia and CVD, there is a high need to develop new therapeutics to effectively lower serum TG levels. Both Aims 1 and 2 align with the mission of NHLBI to improve the medical care for CVD in diverse ethnic groups. The ultimate goals of my Research Training Plan are to discover and functionally characterize population-specific biomarkers, improving prognosis, prevention, and treatment of dyslipidemias; and to increase much needed genomic analysis of CVD in the Latinos, expediting personalized medicine of CVD in this underrepresented but rapidly growing minority.